Molecular aspects of delta opioid receptors

Gendron, Louis; Nagi, Karim; Zeghal, Manel; Giguère, Patrick M.; Piñeyro, Graciela

doi:10.1016/bs.vh.2019.06.001

Cited by 9 publications

(4 citation statements)

References 207 publications

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“…Surprisingly, similar to opioid receptors, vitamin D receptors have a widespread expression within the rat central nervous system and are found in high levels within distinct portions of the sensory, motor and limbic systems (72). Vitamin D receptors, like Cav2 channels, are also expressed in DRG neurons (69,70,170) and whether those receptors could affect opioid signaling by dimerizing with opioid receptors or by directly modulating the expression levels of Cav2 channels or other effectors, like the G protein-coupled inwardly rectifying potassium (GIRK or Kir3) channels involved in the analgesic effects of opioids (171)(172)(173)(174), is still unknown.…”

Section: Calcium Channelsmentioning

confidence: 99%

Vitamin D and Its Potential Interplay With Pain Signaling Pathways

et al. 2020

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About 50 million of the U.S. adult population suffer from chronic pain. It is a complex disease in its own right for which currently available analgesics have been deemed woefully inadequate since ∼20% of the sufferers derive no benefit. Vitamin D, known for its role in calcium homeostasis and bone metabolism, is thought to be of clinical benefit in treating chronic pain without the side-effects of currently available analgesics. A strong correlation between hypovitaminosis D and incidence of bone pain is known. However, the potential underlying mechanisms by which vitamin D might exert its analgesic effects are poorly understood. In this review, we discuss pathways involved in pain sensing and processing primarily at the level of dorsal root ganglion (DRG) neurons and the potential interplay between vitamin D, its receptor (VDR) and known specific pain signaling pathways including nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), epidermal growth factor receptor (EGFR), and opioid receptors. We also discuss how vitamin D/VDR might influence immune cells and pain sensitization as well as review the increasingly important topic of vitamin D toxicity. Further in vitro and in vivo experimental studies will be required to study these potential interactions specifically in pain models. Such studies could highlight the potential usefulness of vitamin D either alone or in combination with existing analgesics to better treat chronic pain.

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Section: Calcium Channelsmentioning

confidence: 99%

Vitamin D and Its Potential Interplay With Pain Signaling Pathways

et al. 2020

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“…With regard to the above mentioned, it should also be noted that receptors with a broad range of interaction affinities with β-arrestin proteins support the idea that the receptor trafficking information is encoded by different phosphorylation sites positioned either individually or in clusters at the receptor C-terminal tail [94][95][96]. These sites can spatially coordinate the constitutive and agonist-induced activity of the receptor toward arrestin proteins.…”

Section: Biased Ghrelin Receptorsmentioning

confidence: 65%

Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity

Nagi

Habib

2021

Cellular Signalling

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Obesity is a global burden and a chronic ailment with damaging overall health effects. Ghrelin, an octanoylated 28 amino acid peptide hormone, is secreted from the oxyntic mucosa of the stomach. Ghrelin acts on regions of the hypothalamus to regulate feeding behavior and glucose homeostasis through its G protein-coupled receptor. Recently, several central pathways modulating the metabolic actions of ghrelin have been reported. While these signaling pathways can be inhibited or activated by antagonists or agonists, they can also be discriminatingly activated in a "biased" response to impart different degrees of activation in distinct pathways downstream of the receptor. Here, we review recent ghrelin biased signaling findings as well as characteristics of ghrelin hormone and its receptors pertinent for biased signaling. We then evaluate the feasibility for ghrelin receptor biased signaling as a strategy for the development of effective pharmacotherapy in obesity treatment.

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“…The pocket integrates three important well-known molecular switches, FxxCW 6.48 xP, NPXXY 7.53 , and a cluster of residues making a hydrogen-bonding network; it should be noted that only the DRY motif is excluded from the pocket. Depending on the receptor, five or six of the 15 residues lining the pocket are involved in the direct interaction with the Na + ion, or through coordination between water and the Na + ion. , While the D95A 2.50 mutant abrogated the observed functional effect, it did not strongly reduce binding, thus excluding it as a direct interacting residue with our modulators. Some of the residues forming the pocket have been found to increase the activity of our modulators, such as N131V 3.35 , S135A 3.39 , and S311A 7.46 , and may even rescue the loss of DADLE efficacy.…”

Section: Discussionmentioning

confidence: 91%

“…Indeed, as this publication demonstrates, we found that the mu- (MOR) and delta- (DOR) opioid receptors were strongly modulated by some of the derivatives tested. We chose to further characterize the interaction at the delta-opioid receptor, given our previous structural studies of the Na + -cavity on said receptor. ,, Our work provides a clear illustration of the direct activity of the derivatives at DOR, with MIA and HMA demonstrating the best agonist allosteric modulator activity (Ago-PAM). In contrast, zoniporide was found to have very weak agonist activity but still retains a similar PAM in the presence of the prototypic agonist DADLE.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor

et al. 2022

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Existing pharmacotherapies acting on the opioid receptor system have been extensively used to treat chronic pain and addictive disorders. Nevertheless, the adverse side effects associated with opioid therapy underscore the need for concerted measures to develop safer analgesics. A promising avenue of research stems from the characterization of a sodium-dependent allosteric regulation site housed within the delta-opioid receptor and several other G protein-coupled receptors (GPCRs), thereby revealing the presence of a cluster of sodium and water molecules lodged in a cavity thought to be present only in the inactive conformation of the receptor. Studies into the structure–function relationship of said pocket demonstrated its critical involvement in the functional control of GPCR signaling. While the sodium pocket has been proposed to be present in the majority of class A GPCRs, the shape of this allosteric cavity appears to have significant structural variation among crystallographically solved GPCRs, making this site optimal for the design of new allosteric modulators that will be selective for opioid receptors. The size of the sodium pocket supports the accommodation of small molecules, and it has been speculated that promiscuous amiloride and 5′-substituted amiloride-related derivatives could target this cavity within many GPCRs, including opioid receptors. Using pharmacological approaches, we have described the selectivities of 5′-substituted amiloride-related derivatives, as well as the hitherto undescribed activity of the NHE1 inhibitor zoniporide toward class A GPCRs. Our investigations into the structural features of the delta-opioid receptor and its ensuing signaling activities suggest a bitopic mode of overlapping interactions involving the orthosteric site and the juxtaposed Na + pocket, but only at the active or partially active opioid receptor.

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Molecular aspects of delta opioid receptors

Cited by 9 publications

References 207 publications

Vitamin D and Its Potential Interplay With Pain Signaling Pathways

Vitamin D and Its Potential Interplay With Pain Signaling Pathways

Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity

Functional Characterization of Sodium Channel Inhibitors at the Delta-Opioid Receptor

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